Method for preparing prostaglandin derivative

ABSTRACT

Disclosed is a method for preparing a prostaglandin derivative of formula (A): 
                         
which comprises reacting an aldehyde represented by formula (1):
 
                         
with a 2-oxoalkyl phosphonate in a reaction solvent under the presence of alkali hydroxide as sole base. By carrying out the reaction using an alkali hydroxide as sole base in the reaction system, the desired prostaglandin derivative can be obtained by simple procedures and with high yield.

CROSS REFERENCE TO RELATED APPLICATION

This is a divisional of application Ser. No. 11/703,138 filed Feb. 7,2007, claiming benefit of Provisional Appln. No. 60/765,728 filed Feb.7, 2006, the disclosures of which are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to a method for preparing a prostaglandinderivative that is useful for the treatment of a variety of diseases orconditions, or as synthesis intermediates for manufacturingtherapeutically active compounds.

ART RELATED

Prostaglandin has a prostanoic acid structure indicated by the formula:

and there are many prostaglandins having a variety of therapeuticeffects.

The Corey method is a conventional, well-known and representative methodfor prostaglandin synthesis.

The Corey method includes a process wherein an α,β-unsaturatedketolactone (III) is obtained from a Corey lactone (I) via a Coreyaldehyde (II):

wherein Ar is an aromatic group.

That is to say, the Corey lactone (I) is oxidized to yield the Coreyaldehyde (II), then reacted with an anion (enolate) prepared by thereaction of dimethyl 2-oxoalkyl phosphonate and sodium hydride, to givethe α,β-unsaturated ketone (III).

In particular, when introducing an ω chain into an aldehyde in theprocess of synthesizing a prostaglandin compound having a halogen atomon the ω chain, it is difficult to ensure a sufficient yield forapplying the method to the industrial use. Prostaglandin compoundshaving a halogen atom on the ω chain have therapeutic effects and thesynthesis methods thereof have been studied (U.S. Pat. Nos. 6,583,174,5,284,858 and 5,739,161, the contents of these references are hereinincorporated by reference.).

Formerly, copper enolate and thallium enolate were tried to use tointroduce an ω chain that was substituted with a halogen atom into theprostaglandin structure in high yield. However, the attempt using copperenolate failed to achieve sufficient yield. Although the attempt usingthallium enolate could significantly increase the yield, thalliumenolate was not preferably used in the industrial process owing to thetoxicity of thallium per se and the high cost of thallium compounds.

Thereafter, an increase in yield has become possible by reacting in thepresence of a base such as sodium hydride and a zinc compound (U.S. Pat.Nos. 5,229,529 and 5,468,880, the contents of these references areherewith incorporated by reference). This method requires metal exchangewith zinc after preparation of the enolate from the phosphonate and thebase, such that the cumbersomeness and complexity of the operationalprocedure has not been resolved. In addition, as the yield decreases bycontamination of the reaction system with moisture, dehydration of thereaction solvent and drying of the zinc compound are mandatory.Moreover, as an industrial process, problems are still remained, suchas, generation of liquid wastes containing zinc ion.

SUMMARY OF THE INVENTION

An object of the present invention is to provide a simple, highlyefficient and industrially applicable method for preparing aprostaglandin derivative, especially, those having one or more halogenatoms on the ω chain.

Accordingly, the present invention provides a method for preparing aprostaglandin derivative of formula (A):

-   -   wherein A₁ is a hydrogen atom or a protecting group for a        hydroxy group;    -   Y is —OA₂, wherein A₂ is a hydrogen or a protecting group for a        hydroxy group;    -   W is —R₁-Q, wherein R₁ is a saturated or unsaturated bivalent        lower or medium aliphatic hydrocarbon residue, which is        unsubstituted or substituted with halogen, lower alkyl, hydroxy,        oxo, aryl or heterocyclic, and at least one of carbon atoms in        the aliphatic hydrocarbon is optionally substituted by oxygen,        nitrogen or sulfur, Q is —CH₃, —COCH₃,

-   —OH, —COOH or a functional derivative thereof; or

-   Y and W may both together form a group represented by the formula:

-   -   wherein R₁′ is a bivalent saturated or unsaturated lower to        medium aliphatic hydrocarbon residue

R₃ is a saturated or unsaturated lower to medium aliphatic hydrocarbonresidue that is unsubstituted or substituted with a lower alkoxy, alower alkanoyloxy, a cyclo(lower)alkyl, a cyclo(lower)alkyloxy, an aryl,an aryloxy, a heterocyclic or a heterocyclicoxy; a cyclo(lower)alkylgroup; a cyclo(lower)alkyloxy group; an aryl group; an aryloxy group; aheterocyclic group; a heterocyclicoxy group;

-   -   X₁ and X₂ are a hydrogen, a lower alkyl group or a halogen; and    -   Z is ═CH— or —CH═CH—,        provided that —OA₁ and Q may together form

-   which comprises reacting an aldehyde represented by formula (1):

-   -   wherein Y, W and A₁ have the same meanings as above;    -   B is a single bond or —CH₂—,        with a 2-oxoalkyl phosphonate represented by formula (2):

-   -   wherein X₁, X₂ and R₃ have the same meanings as above; and    -   R₂ is a lower alkyl group;

-   in a reaction solvent under the presence of alkali hydroxide as sole    base.

In another aspect of the present invention, the invention provides novelprostaglandin derivatives including:

-   7-[(1R,2R,3R,5S)-2-(4,4-difluoro-3-hydroxyoctyl)-5-hydroxy-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanoic    acid.-   Benzyl 7-[(1R,2R,3R,5S)-2-(4,4-difluoro-3-hydroxy    octyl)-5-hydroxy-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate.-   Benzyl    7-[(1R,3R,6R,7R)-3-(1,1-difluoropentyl)-3-hydroxy-2-oxabicyclo[4.3.0]nonan-8-on-7-yl]heptanate.-   Methyl 7-[(1R,2S,3R,5S)-2-(t-butyldimethylsilyloxy    methyl)-5-hydroxy-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate.-   Methyl 7-[(1R,2S,3R,5S)-5-acetoxy-2-(t-butyl    dimethylsilyloxymethyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate.    Those compounds are useful for manufacturing a therapeutically    effective prostaglandin derivative.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In the above formulae, the term “unsaturated” in R₁, R₁′ and R₃ means tocontain at least one or more double-bond and/or triple-bond alone,separately or contiguously, as bonds between carbon atoms of the mainchain and/or side chain. According to the general nomenclature,unsaturations between two contiguous positions are indicated byrepresenting the younger position number, and unsaturations between twonon-contiguous positions are indicated by representing both positionnumbers.

The term “lower to medium aliphatic hydrocarbon” means a hydrocarbonhaving a straight or branched chain having 1 to 14 carbon atoms (for aside chain, 1 to 3 carbon atoms are preferable) and preferably 1 to 10,especially 6 to 10 carbon atoms for R₁; 1 to 10, especially, 1 to 6carbon atoms for R₁′; and 1 to 10, especially 1 to 8 carbon atoms forR₃.

The term “halogen” comprises fluorine, chlorine, bromine and iodide.

The term “lower” comprises groups having 1 to 6 carbon atoms, unlessspecifically stated otherwise.

The term “lower alkyl” comprises straight chain or branched chainsaturated hydrocarbon groups having 1 to carbon atoms, for instance,methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl,pentyl and hexyl.

The term “lower alkoxy” means lower alkyl-O—, in which lower alkyl hasthe same meaning as above.

The term “lower alkanoyloxy” means groups indicated by the formulaRCO—O— (herein, RCO— is acyls generated by oxidation of lower alkylssuch as those described above, for instance, acetyl).

The term “cyclo(lower)alkyl” comprises cyclic groups generated bycyclization of lower alkyl groups such as those described above,containing three or more carbon atoms, for instance, cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl.

The term “cyclo(lower)alkyloxy” means cyclo(lower)alkyl-O—, in whichcyclo(lower)alkyl has the same meaning as above.

The term “aryl” comprises aromatic hydrocarbon ring group that may beunsubstituted or non-substituted, preferably monocyclic, for instance,phenyl, tolyl and xylyl can be given as examples. Substituents includehalogens and halogen-substituted lower alkyl groups (herein, halogensand lower alkyl groups have the aforementioned meanings).

The term “aryloxy” means groups indicated by the formula ArO— (herein,Ar is aryl groups such as those described above).

The term “heterocyclic group” may include mono- to tri-cyclic,preferably monocyclic heterocyclic group which is 5 to 14, preferably 5to 10 membered ring having optionally substituted carbon atom and 1 to4, preferably 1 to 3 of 1 or 2 type of hetero atoms selected fromnitrogen, oxygen and sulfur. Examples of the heterocyclic group includefuryl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,imidazolyl, pyrazolyl, furazanyl, pyranyl, pyridyl, pyridazinyl,pyrimidyl, pyrazinyl, 2-pyrrolinyl, pyrrolidinyl, 2-imidazolinyl,imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, piperidino, piperazinyl,morpholino, indolyl, benzothienyl, quinolyl, isoquinolyl, purinyl,quinazolinyl, carbazolyl, acridinyl, phenanthridinyl, benzimidazolyl,benzimidazolinyl, benzothiazolyl, phenothiazinyl. Examples of thesubstituent in this case include halogen, and halogen substituted loweralkyl group, wherein halogen and lower alkyl group are as describedabove.

The term “heterocyclicoxy group” means a group represented by theformula HcO—, wherein Hc is a heterocyclic group as described above.

The term “functional derivative” for Q includes salts, preferablypharmaceutically acceptable salts, ethers, esters and amides.

As suitable “pharmaceutically acceptable salts”, including non-toxicsalts commonly used, salts with inorganic bases, for instance, alkalinemetal salts (sodium salt, potassium salt and the like), alkaline earthmetal salts (calcium salt, magnesium salt and the like), ammonium salts,salts with organic bases, for instance, amine salts (for instance,methylamine salt, dimethylamine salt, cyclohexyl amine salt, benzylaminesalt, piperidine salt, ethylenediamine salt, ethanolamine salt,diethanolamine salt, triethanolamine salt, tris(hydroxymethylamino)ethane salt, monomethyl-mono ethanolamine salt, procaine salt,caffeine salt and the like), basic amino acid salts (for instance,arginine salt, lysine salt and the like), tetra alkyl ammonium salts,and the like, can be given. These salts may be prepared, for instance,from corresponding acids and bases by a conventional reaction or saltexchange.

As examples of ethers, alkyl ethers, for instance, lower alkyl ethers,such as, methyl ether, ethyl ether, propyl ether, isopropyl ether, butylether, isobutyl ether, sec-butyl ether, t-butyl ether, pentyl ether and1-cyclopropyl ethyl ether, medium or higher alkyl ethers, such as, octylether, diethyl hexyl ether, lauryl ether, cetyl ether, unsaturatedethers, such as, oleyl ether and linolenyl ether, lower alkenyl ethers,such as, vinyl ether and allyl ether, lower alkynyl ethers, such as,ethinyl ether and propynyl ether, hydroxy(lower)alkyl ethers, such as,hydroxyethyl ether and hydroxy isopropyl ether, lower alkoxy(lower)alkylethers, such as, methoxy methyl ether and 1-methoxy ethyl ether, and,for instance, optionally substituted aryl ethers, such as, phenyl ether,tosyl ether, t-butyl phenyl ether, salicyl ether, 3,4-dimethoxyphenylether and benzamide phenyl ether, and aryl(lower)alkyl ethers such asbenzyl ether, trityl ether and benzhydryl ether, can be cited.

As esters, aliphatic esters including lower alkyl esters, such as,methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester,isobutyl ester, sec-butyl ester, t-butyl ester, pentyl ester and1-cyclopropyl ethyl ester, lower alkenyl esters, such as, vinyl esterand allyl ester, lower alkynyl esters, such as, ethinyl ester andpropynyl ester, hydroxy (lower)alkyl esters, such as, hydroxyethylester, lower alkoxy (lower)alkyl esters, such as, methoxy methyl esterand 1-methoxy ethyl ester; and for instance, optionally substituted arylesters, such as, phenyl ester, tolyl ester, t-butyl phenyl ester,salicyl ester, 3,4-dimethoxyphenyl ester and benzamide phenyl ester, andaryl(lower)alkyl esters such as, benzyl ester, trityl ester andbenzhydryl ester can be cited.

The amides of Q means a group represented by the formula —CONR′R″,wherein R′ and R″ are, respectively, a hydrogen, lower alkyl, aryl,alkyl- or aryl-sulfonyl, lower alkenyl and lower alkynyl, and forinstance, lower alkyl amides, such as, methyl amide, ethyl amide,dimethylamide and diethylamide, aryl amides, such as, anilide andtoluidide, alkyl- or aryl-sulfonyl amides, such as, methyl sulfonylamide, ethyl sulfonyl amide and tolyl sulfonyl amide, and the like, canbe cited.

Preferred examples for Q are —COOH, pharmaceutically acceptable salts,esters and amides thereof.

Preferred example for B is a single bond, and preferred example for Z is═CH—.

Preferred examples of R₁ are hydrocarbons having 1 to 10 carbon atoms,and especially, hydrocarbons having 6 to 10 carbon atoms. In addition,at least one carbon atom in the aliphatic hydrocarbon may be optionallysubstituted by an oxygen, a nitrogen or a sulfur.

Examples of R₁ include, for example, the following groups:

-   —CH₂—CH₂—CH₂—CH₂—CH₂—CH₂—,-   —CH₂—CH═CH—CH₂—CH₂—CH₂—,-   —CH₂—CH₂—CH₂—CH₂—CH═CH—,-   —CH₂—C≡C—CH₂—CH₂—CH₂—,-   —CH₂—CH₂—CH₂—CH₂—CH(CH₃)—CH₂—,-   —CH₂—CH₂—CH₂—CH₂—O—CH₂—,-   —CH₂—CH═CH—CH₂—O—CH₂—,-   —CH₂—C≡C—CH₂—O—CH₂—,-   —CH₂—CH₂—CH₂—CH₂—O—CH₂—CH₂—CH₂—,-   —CH₂—CH═CH—CH₂—CH₂—CH₂—CH₂—,-   —CH₂—CH₂—CH₂—CH₂—CH₂—CH═CH—,-   —CH₂—C≡C—CH₂—CH₂—CH₂—CH₂—,-   —CH₂—CH₂—CH₂—CH₂—CH₂—CH(CH₃)—CH₂—,-   —CH₂—CH₂—CH₂—CH₂—CH₂—CH₂—CH₂—CH₂—,-   —CH₂—CH═CH—CH₂—CH₂—CH₂—CH₂—CH₂—,-   —CH₂—CH₂—CH₂—CH₂—CH₂—CH₂—CH═CH—,-   —CH₂—C≡C—CH₂—CH₂—CH₂—CH₂—CH₂—, and-   —CH₂—CH₂—CH₂—CH₂—CH₂—CH₂—CH(CH₃)—CH₂—.

Preferred R₃ is an unsubstituted hydrocarbon having 1 to 10, andpreferably 1 to 8 carbon atoms.

For X₁ and X₂, cases where at least one is a halogen are preferred, inparticular, cases where both are halogen, especially fluorine, arepreferred.

Examples of A₁ and A₂ may comprise the entirety of those groups formingprotecting groups for hydroxy groups, and a protecting group for ahydroxy group means a functional group that is introduced to inactivatethe hydroxy group against a specific reaction in order to avoid anundesirable chemical reaction, and as long as it conforms to thispurpose, is not limited in particular. For instance, methyl group,methoxy methyl group, ethyl group, 1-ethoxy ethyl group, benzyl group,substituted benzyl group, allyl group, tetrapyranyl group, t-butyldimethyl silyl group, triethyl silyl group, triisopropyl silyl group,diphenyl methyl silyl group, formyl group, acetyl group, substitutedacetyl group, benzoyl group, substituted benzoyl group, methyloxycarbonyl group, benzyloxy carbonyl group, t-butyloxy carbonyl group,allyloxy carbonyl group, and the like, can be cited.

According to the present invention, a method for preparing aprostaglandin derivative, especially, a prostaglandin derivative havingone or more halogen on the ω chain represented by formula (A) isobtained by reacting an aldehyde (1) and a 2-oxoalkylphosphonate (2) inthe presence of an alkali hydroxide as sole base in the reaction system.

In a preferred embodiment, a prostaglandin derivative represented byformula (B):

may be prepared using an aldehyde represented by formula (3):

-   -   wherein A₁, A₂, B, R₁, Q, X₁, X₂ and Z have the same meanings as        described above.

In preferred embodiment, a prostaglandin derivative of formula (C):

may be prepared using an aldehyde of formula (4):

-   -   wherein A₁, B, R₃, X₁, X₂ and Z have the same meanings as        described above.

By carrying out the reaction using an alkali hydroxide as sole base inthe reaction system, the target product, prostaglandin derivative can beobtained in high yield by simple procedures. There is no need to use aheavy metal reagent like zinc compound. On the other hand, for instancewhen a base such as alkaline metal hydroxide is used alone,prostaglandin derivative having a halogen atom on the ω chain, inparticular, cannot be obtained effectively.

According to the present invention, alkali hydroxide may be any of thoseshown by the formula:M-OH or M(OH)₂;

wherein M is an alkaline metal or an alkaline earth metal. In moredetail, lithium hydroxide, sodium hydroxide, potassium hydroxide,calcium hydroxide, strontium hydroxide, barium hydroxide, and the like,can be cited, and preferably lithium hydroxide may be used.

The amount of alkali hydroxide used is preferably on the order of 0.9 to1 equivalent with respect to 2-oxoalkyl phosphonate represented byformula (2). In addition, the amount of 2-oxoalkyl phosphonate (2) usedin the reaction is preferably on the order of 1 to 3 equivalents withrespect to the aldehyde represented by formula (1), and especially, onthe order of 1.1 to 2 equivalents.

The reaction solvent is not limited in particular, and for instance,ethers, such as, ethyl ether, dimethoxy ethane, t-butyl methyl ether,diisopropyl ether, tetrahydrofuran and dioxane, aromatic compounds, suchas, benzene and toluene, and halogenated hydrocarbons such asdichloroethane are preferred, and ethers are particularly preferred.

The amount of reaction solvent used in the reaction may be 1 to 100 mlwith respect to 1 g of aldehyde (1), and especially, 10 to 50 ml.

The reaction temperature may be 0 to 100° C., and especially, 20 to 80°C.

The reaction time may be 1 to 100 hours, especially 10 to 50 hours whenat least one of X₁ and X₂ is a halogen, in particular a fluorine, andespecially, 1 to 5 hours extent when X₁ and X₂ are other than halogen.

According to the invention, the reaction system may comprise water. Theamount of water added to the reaction may be 0.5 to 10% with respect tothe reaction solvent, and especially, of 1 to 4%.

EXAMPLES

The present invention will be explained in more detail by means of thefollowing examples, which are illustrated by way of example only andnever intended to limit the scope of the present invention.

Example 1a

To a solution of dimethyl(3,3-difluoro-2-oxoheptyl)phosphonate (1)(50.50 g, 195.6 mmol) in t-butyl methyl ether (750 ml), lithiumhydroxide monohydrate (7.94 g, 189 mmol) was added and the mixture wasstirred for one hour at room temperature. A solution of methyl7-[(1R,2R,3R,5S)-5-acetoxy-2-formyl-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate(2) (52.00 g, 130.5 mmol) in t-butyl methyl ether (150 ml) and water (27ml) were added thereto, and the mixture was heat refluxed forapproximately 49 hours (internal temperature: approximately 53° C.).After cooling to room temperature, water (300 ml) was added and themixture was stirred, let to stand and then separated into two layers.The aqueous layer was extracted twice with ethyl acetate (200 ml). Theorganic layers were combined, washed twice with saturated aqueous sodiumchloride (300 ml), and dried with anhydrous magnesium sulfate (50 g).After concentration under reduced pressure, the residue was purified bysilica gel column chromatography (Fuji Silysia BW-300: 1805 g; ethylacetate:hexane =1:4). The fractions containing impurities werere-purified by silica gel column chromatography (Fuji Silysia BW-300:580 g; ethyl acetate:hexane =1:4), to give methyl7-[(1R,2R,3R,5S)-5-acetoxy-2-((E)-4,4-difluoro-3-oxo-1-octenyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate(3) (62.38 g; 117.6 mmol; yield: 90.1%) as a pale yellow oil.

¹H-NMR (200 MHz, CDCl₃): δ (ppm): 7.10 (0.5H, dd, J=15.7, 7.0 Hz), 7.05(0.5H, dd, J=15.7, 7.4 Hz), 6.67 (0.5H, d, J=15.7 Hz), 6.62 (0.5H, d,J=15.7 Hz), 5.19-5.08 (1H, m), 4.61-4.46 (1H, m), 4.18-3.93 (1H, m),3.88-3.62 (1H, m), 3.66 (3H, s), 3.51-3.31 (1H, m), 2.87-2.36 (2H, m),2.29 (2H, t, J=7.4 Hz), 2.15-1.11 (24H, m), 2.07 (3H, s), 0.92 (3H, t,J=6.9 Hz)

Example 1b

To a solution of dimethyl (3,3-difluoro-2-oxoheptyl)phosphonate (1)(0.243 g, 941 mmol) in t-butyl methyl ether (4 ml), lithium hydroxidemonohydrate (38.2 mg, 910 mmol) was added and the mixture was stirredfor one hour at room temperature. A solution of methyl7-[(1R,2R,3R,5S)-5-acetoxy-2-formyl-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate(2) (0.250 g, 627 mmol) in t-butyl methyl ether (3 ml) was addedthereto, and the mixed solution was heat refluxed for approximately 42hours. After cooling to room temperature, the reaction mixture was addedto water and extracted twice with t-butyl methyl ether. The organiclayers were combined, sequentially washed with saturated sodiumbicarbonate water and saturated aqueous sodium chloride, and then driedwith anhydrous magnesium sulfate. After concentration under reducedpressure, the residue was purified by silica gel column chromatography(Fuji Silysia FL-60D: 100 g; ethyl acetate:hexane =1:3), to give methyl7-[(1R,2R,3R,5S)-5-acetoxy-2-((E)-4,4-difluoro-3-oxo-1-octenyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate(3) (0.173 g; 326 mmol; yield: 52.0%).

Comparative Example 1

To a solution of dimethyl (3,3-difluoro-2-oxoheptyl)phosphonate (1)(1.051 g, 4.070 mmol) in anhydrous t-butyl methyl ether (16 ml), lithiumhydride (30.3 mg, 3.81 mmol) was added and the mixture was stirred forapproximately 6 hours at room temperature. A solution of methyl7-[(1R,2R,3R,5S)-5-acetoxy-2-formyl-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (2) (0.903 g, 2.27 mmol) in anhydroust-butyl methyl ether (3 ml) was added thereto, and the mixed solutionwas heat refluxed for approximately 48 hours. After cooling to roomtemperature, water was added to the solution and the mixture wasstirred, let to stand and then separated into two layers. The aqueouslayer was extracted twice with ethyl acetate. The organic layers werecombined, sequentially washed with 3% aqueous sodium chloride andsaturated aqueous sodium chloride, and then dried with anhydrousmagnesium sulfate. After concentration under reduced pressure, theresidue was purified by silica gel column chromatography (Fuji SilysiaBW-300SP: 36 g/15 g/18 g; ethyl acetate:hexane =1:4) three times, togive methyl7-[(1R,2R,3R,5S)-5-acetoxy-2-((E)-4,4-difluoro-3-oxo-1-octenyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate(3) (0.257 g; 0.484 mmol; yield: 21.3%).

Example 2a

To a solution of dimethyl (3,3-difluoro-2-oxoheptyl)phosphonate (1)(1.050 g, 4.066 mmol) in tetrahydrofuran (16 ml), lithium hydroxidemonohydrate (0.161 g, 3.84 mmol) was added and the mixture was stirredat room temperature for approximately 1.2 hours. A solution of methyl7-[(1R,2R,3R,5S)-5-acetoxy-2-formyl-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate(2) (0.903 g, 2.27 mmol) in tetrahydrofuran (3 ml), and water (0.57 ml)were added thereto, and the mixed solution was heat refluxed forapproximately 48 hours. After cooling to room temperature, approximatelyhalf of the solvent was evaporated from the solution under reducedpressure. Ethyl acetate and water were added to the solution and thesolution was stirred, let to stand and then separated into two layers.The aqueous layer was extracted twice with ethyl acetate. The organiclayers were combined, sequentially washed with 3% aqueous sodiumchloride and saturated aqueous sodium chloride, and then dried withanhydrous magnesium sulfate. After concentration under reduced pressure,the residue was purified by silica gel column chromatography (FujiSilysia BW-300SP 27 g, ethyl acetate:hexane =1:4). The fractionscontaining impurities were re-purified by silica gel columnchromatography (Fuji Silysia BW-300SP: 6 g; ethyl acetate:hexane=1:4),to give methyl7-[(1R,2R,3R,5S)-5-acetoxy-2-((E)-4,4-difluoro-3-oxo-1-octenyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate(3) (0.719 g; 1.35 mmol; yield: 59.8%).

Example 2b

A solution of dimethyl (3,3-difluoro-2-oxoheptyl)phosphonate (1) (1.110g, 4.299 mmol) in tetrahydrofuran (17 ml) was added with lithiumhydroxide monohydrate (0.171 g, 4.08 mmol), and the mixture was stirredfor approximately 1.2 hours at room temperature. A solution of methyl7-[(1R,2R,3R,5S)-5-acetoxy-2-formyl-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (2) (0.971 g, 2.44 mmol) intetrahydrofuran (3 ml), and water (0.32 ml) were added thereto, and themixed solution was heat refluxed for approximately 48 hours. Aftercooling to room temperature, the solution was concentrated under reducedpressure. Ethyl acetate and water were added to the residue and thesolution was stirred, let to stand and then separated into two layers.The aqueous layer was extracted twice with ethyl acetate. The organiclayers were combined, sequentially washed with 3% aqueous sodiumchloride and saturated aqueous sodium chloride, and then dried withanhydrous magnesium sulfate. After concentration under reduced pressure,the residue was purified by silica gel column chromatography (FujiSilysia BW-300SP: 38 g; ethyl acetate:hexane =1:4), to give methyl7-[(1R,2R,3R,5S)-5-acetoxy-2-((E)-4,4-difluoro-3-oxo-1-octenyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate(3) (0.722 g; 1.36 mmol; yield: 55.8%).

Example 2c

A solution of dimethyl (3,3-difluoro-2-oxoheptyl)phosphonate (1) (1.110g, 4.299 mmol) in tetrahydrofuran (17 ml) was added with lithiumhydroxide monohydrate (0.171 g, 4.08 mmol), and the mixture was stirredfor approximately 1.2 hours at room temperature. A solution of methyl7-[(1R,2R,3R,5S)-5-acetoxy-2-formyl-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate(2) (0.962 g, 2.41 mmol) in tetrahydrofuran (3 ml) was added thereto,and the mixed solution was heat refluxed for approximately 48 hours.After cooling to room temperature, the solution was concentrated underreduced pressure. Ethyl acetate and water were added to the residue andstirred, then, the mixture was let to stand and separated into twolayers. The aqueous layer was extracted twice with ethyl acetate. Theorganic layers were combined, sequentially washed with 3% aqueous sodiumchloride and saturated aqueous sodium chloride, and then dried withanhydrous magnesium sulfate. After concentration under reduced pressure,the residue was purified by silica gel column chromatography (FujiSilysia BW-300SP: 38 g; ethyl acetate:hexane =1:4), to give methyl7-[(1R,2R,3R,5S)-5-acetoxy-2-((E)-4,4-difluoro-3-oxo-1-octenyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate(3) (0.517 g; 0.973 mmol; yield: 40.4%).

Comparative Example 2

To a solution of dimethyl (3,3-difluoro-2-oxoheptyl)phosphonate (1)(0.453 g, 1.75 mmol) in anhydrous THF (7 ml), sodium hydride (60%,dispersion in mineral oil, 70 mg, 1.75 mmol) was added and stirred for15 minutes at room temperature. A solution of methyl7-[(1R,2R,3R,5S)-5-acetoxy-2-formyl-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate(2) (0.175 g, 439 mmol) in anhydrous THF (3 ml) was added thereto, andthe mixed solution was heat refluxed for approximately 4 hours. Only atrace amount of the target product (3) was obtained.

Example 3

To a solution of dimethyl (3,3-difluoro-2-oxoheptyl)phosphonate (1)(1.052 g, 4.074 mmol) in 1,4-dioxane (16 ml), lithium hydroxidemonohydrate (0.160 g, 3.81 mmol) was added and stirred for approximately1.2 hours at room temperature. A solution of methyl7-[(1R,2R,3R,5S)-5-acetoxy-2-formyl-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (2) (0.902 g, 2.26 mmol) in 1,4-dioxane(3 ml) and water (0.57 ml) were added thereto, and the mixed solutionwas heat refluxed for approximately 48 hours. After cooling to roomtemperature, approximately half of the solvent was evaporated underreduced pressure. Ethyl acetate and water were added to the residue andthe solution was stirred, let to stand and then separated into twolayers. The aqueous layer was extracted twice with ethyl acetate. Theorganic layers were combined, sequentially washed with 3% aqueous sodiumchloride and saturated aqueous sodium chloride, and then dried withanhydrous magnesium sulfate. After concentration under reduced pressure,the residue was purified by silica gel column chromatography (FujiSilysia BW-300SP: 36 g; ethyl acetate:hexane =1:4). The fractionscontaining impurities were re-purified by silica gel columnchromatography (Fuji Silysia BW-300SP: 6 g; ethyl acetate:hexane =1:4)to give methyl7-[(1R,2R,3R,5S)-5-acetoxy-2-((E)-4,4-difluoro-3-oxo-1-octenyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate(3) (0.671 g; 1.26 mmol; yield: 55.9%).

Example 4a

To a solution of dimethyl (3,3-difluoro-2-oxoheptyl)phosphonate (1)(1.109 g, 4.295 mmol) in t-butyl methyl ether (17 ml), sodium hydroxide(0.164 g, 4.10 mmol) was added and the mixture was stirred forapproximately 1.2 hours at room temperature. A solution of methyl7-[(1R,2R,3R,5S)-5-acetoxy-2-formyl-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate(2) (0.955 g, 2.40 mmol) in t-butyl methyl ether (3 ml), and water (0.32ml) were added thereto, and the mixed solution was heat refluxed forapproximately 48 hours. After cooling to room temperature, water (5.6ml) was added to the solution and stirred, and then, let to stand andseparated into two layers. The aqueous layer was extracted twice withethyl acetate (4 ml). The organic layers were combined, sequentiallywashed with 3% aqueous sodium chloride (6 ml) and saturated aqueoussodium chloride (6 ml), and then dried with anhydrous magnesium sulfate.After concentration under reduced pressure, the residue was purified bysilica gel column chromatography (Fuji Silysia BW-300SP: 33 g; ethylacetate:hexane =1:4) to give methyl7-[(1R,2R,3R,5S)-5-acetoxy-2-((E)-4,4-difluoro-3-oxo-1-octenyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate(3) (1.079 g; 2.033 mmol; yield: 84.8%).

Example 4b

To a solution of dimethyl (3,3-difluoro-2-oxoheptyl)phosphonate (1)(1.113 g, 4.31 mmol) in t-butyl methyl ether (17 ml), potassiumhydroxide (0.225 g, 4.00 mmol) was added and the mixture was stirred forapproximately 1.2 hours at room temperature. A solution of methyl7-[(1R,2R,3R,5S)-5-acetoxy-2-formyl-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (2) (0.965 g, 2.42 mmol) in t-butylmethyl ether (3 ml) solution, and water (0.32 ml) were added thereto.The mixed solution was heat refluxed for approximately 48 hours. Aftercooling to room temperature, water (5.6 ml) was added to the solutionand the mixture was stirred, let to stand and then separated into twolayers. The aqueous layer was extracted twice with ethyl acetate (4 ml).The organic layers were combined, sequentially washed with 3% aqueoussodium chloride (6 ml) and saturated aqueous sodium chloride (6 ml), anddried with anhydrous magnesium sulfate. After concentration underreduced pressure, the residue was purified by silica gel columnchromatography (Fuji Silysia BW-300SP: 33 g; ethyl acetate:hexane =1:4)to give methyl7-[(1R,2R,3R,5S)-5-acetoxy-2-((E)-4,4-difluoro-3-oxo-1-octenyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate(3) (1.035 g; 1.950 mmol; yield: 80.6%).

Example 5a

To a solution of dimethyl(3,3-difluoro-5S-methyl-2-oxoheptyl)phosphonate (4) (74.7 g, 274 mmol)in t-butyl methyl ether (1120 ml), lithium hydroxide monohydrate (11.5g, 273 mmol) was added and the mixture was stirred for one hour at roomtemperature. A solution of methyl7-[(1R,2R,3R,5S)-5-acetoxy-2-formyl-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate(2) (64.02 g, 160.6 mmol) in t-butyl methyl ether (278 ml) and water(21.7 ml) were added thereto, and the mixed solution was heat refluxedfor approximately 31 hours (internal temperature: approximately 53° C.).After cooling to room temperature, water (351 ml) was added to thesolution and the mixture was stirred, let to stand and then separatedinto two layers. The aqueous layer was extracted twice with ethylacetate (234 ml). The organic layers were combined, washed twice withsaturated aqueous sodium chloride (351 ml), and dried with anhydrousmagnesium sulfate (55 g). After concentration under reduced pressure,the residue was purified by silica gel column chromatography (FujiSilysia BW-300: 2110 g; ethyl acetate:hexane =1:4 to 1:2). The fractionscontaining impurities were re-purified by silica gel columnchromatography (Fuji Silysia BW-300: 850 g; ethyl acetate:hexane =1:4 to1:2) to give methyl7-[(1R,2R,3R,5S)-5-acetoxy-2-((E)-4,4-difluoro-6S-methyl-3-oxo-1-octenyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate(5) (75.03 g; 137.8 mmol; yield: 85.8%) as a pale yellow oil.

¹H-NMR (200 MHz, CDCl₃): δ (ppm): 7.10 (0.5H, dd, J=15.6, 6.5 Hz), 7.05(0.5H, dd, J=15.6, 7.0 Hz), 6.68 (0.5H, d, J=15.6 Hz), 6.63 (0.5H, d,J=15.6 Hz), 5.19-5.09 (1H, m), 4.61-4.46 (1H, m), 4.19-3.93 (1H, m),3.88-3.60 (1H, m), 3.66 (3H, s), 3.50-3.31 (1H, m), 2.87-2.36 (2H, m),2.28 (2H, t, J=7.5 Hz), 2.15-1.03 (23H, m), 2.07 (3H, s), 0.97 (3H, t,J=6.4 Hz), 0.88 (3H, t, J=7.3 Hz)

Example 5b

To a solution of dimethyl (3,3-difluoro-2-oxo-3-phenylpropyl)phosphonate(6) (0.262 g, 0.942 mmol) in t-butyl methyl ether (7 ml), lithiumhydroxide monohydrate (38.2 mg, 0.910 mmol) was added and the mixturewas stirred for one hour at room temperature. A solution of methyl7-[(1R,2R,3R,5S)-5-acetoxy-2-formyl-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate(2) (0.250 g, 0.627 mmol) in t-butyl methyl ether (3 ml) and water (0.3ml) were added thereto, and the mixed solution was heat refluxed forapproximately 48 hours. After cooling to room temperature, the reactionmixture was added to water, and extracted twice with t-butyl methylether. The organic layers were combined, sequentially washed with water,saturated sodium bicarbonate water and saturated aqueous sodiumchloride, and then dried with anhydrous magnesium sulfate. Afterconcentration under reduced pressure, the residue was purified by silicagel column chromatography (Merck Art. 9385: 200 g; ethyl acetate:hexane=2:3). The fractions containing impurities were re-purified by silicagel column chromatography (Merck Art. 9385: 120 g; ethyl acetate:hexane=2:3), to give methyl7-[(1R,2R,3R,5S)-5-acetoxy-2-((E)-4,4-difluoro-3-oxo-4-phenyl-1-butenyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate(7) (0.257 g; 0.467 mmol; yield: 74.4%) as a colorless oil.

¹H-NMR (200 MHz, CDCl₃): δ (ppm): 7.60-7.50 (2H, m), 7.50-7.38 (3H, m),7.10 (0.5H, dd, J=16.7, 8.5 Hz), 7.02 (0.5H, dd, J=16.7, 9.5 Hz), 6.66(0.5H, d, J=16.7 Hz), 6.59 (0.5H, d, J=16.7 Hz), 5.17-5.05 (1H, m),4.55-4.48 (0.5H, m), 4.40-4.30 (0.5H, m), 4.16-3.67 (1H, m), 3.66 (3H,s), 3.58-3.13 (2H, m), 2.84-2.35 (2H, m), 2.29 (2H, t, J=7.5 Hz), 2.06(3H, s), 1.93-1.02 (17H, m)

Example 5c

To a solution of dimethyl (3,3-difluoro-2-oxoheptyl)phosphonate (1)(1.816 g, 7.033 mmol) in t-butyl methyl ether (16 ml), lithium hydroxidemonohydrate (0.271 g, 6.46 mmol) was added and the mixture was stirredfor 2.25 hours at room temperature. A solution of methyl(Z)-7-[(1R,2R,3R,5S)-5-acetoxy-2-formyl-3-(2-tetrahydropyranyloxy)cyclopentyl]-5-heptenate(8) (1.554 g, 3.920 mmol) in t-butyl methyl ether (4.7 ml) and water(0.75 ml) were added thereto, and the mixed solution was heat refluxedfor approximately 24 hours. After cooling to room temperature, water wasadded to the solution and the mixture was stirred, let to stand and thenseparated into two layers. The aqueous layer was extracted twice withethyl acetate. The organic layers were combined, sequentially washedwith 3% aqueous sodium chloride and saturated aqueous sodium chloride,and dried with anhydrous magnesium sulfate. After concentration underreduced pressure, the residue was purified by silica gel columnchromatography (Fuji Silysia BW-300SP: 47 g, ethyl acetate:hexane =1:4),to givemethyl(Z)-7-[(1R,2R,3R,5S)-5-acetoxy-2-((E)-4,4-difluoro-3-oxo-1-octenyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]-5-heptenate(9) (1.787 g; 3.380 mmol; yield: 86.2%) as a pale yellow oil.

¹H-NMR (200 MHz, CDCl₃): δ (ppm): 7.11 (0.5H, dd, J=15.7, 7.6 Hz), 7.08(0.5H, dd, J=15.7, 6.9 Hz), 6.68 (0.5H, d, J=15.7 Hz), 6.63 (0.5H, d,J=15.7 Hz), 5.45-5.21 (2H, m), 5.15-5.05 (1H, m), 4.62-4.44 (1H, m),4.19-3.96 (1H, m), 3.88-3.62 (1H, m), 3.66 (3H, s), 3.52-3.32 (1H, m),2.92-2.36 (2H, m), 2.29 (2H, t, J=7.3 Hz), 2.23-1.22 (22H, m), 2.07 (3H,s), 0.92 (3H, t, J=6.9 Hz)

Example 6

To a solution of dimethyl (3,3-difluoro-2-oxoheptyl)phosphonate (1)(0.378 g, 1.50 mmol) in t-butyl methyl ether (5 ml), lithium hydroxidemonohydrate (60.8 mg, 1.45 mmol) was added and the mixture was stirredfor one hour at room temperature. Water (0.15 ml) and(3aR,4R,5R,6aS)-2-oxo-5-phenylcarbonyloxyhexahydrocyclopenta[b]furan-4-carbaldehyde (10) (0.274 g, 1.00 mmol) were addedthereto and the mixed solution was stirred for approximately 3 hours atroom temperature. The reaction mixture was added to water and extractedtwice with t-butyl methyl ether. The organic layers were combined,sequentially washed with water, saturated sodium bicarbonate water andsaturated aqueous sodium chloride, and then dried with anhydrousmagnesium sulfate. After concentration under reduced pressure, theresidue was purified by silica gel column chromatography (Fuji SilysiaBW-300: 100 g; ethyl acetate:hexane =1:2), to give(3aR,4R,5R,6aS)-4-((E)-4,4-difluoro-3-oxo-1-octenyl)-2-oxo-5-phenylcarbonyloxyhexahydrocyclopenta[b]furan(11) (0.201 g; 0.495 mmol; yield: 49.5%) as a colorless oil.

¹H-NMR (200 MHz, CDCl₃): δ (ppm): 8.03-7.95 (2H, m), 7.63-7.39 (3H, m),7.03 (1H, dd, J=15.8, 7.7 Hz), 6.66 (1H, d, J=15.8 Hz), 5.30-5.41 (1H,m), 5.20-5.06 (1H, m), 3.08-2.82 (3H, m), 2.74-2.26 (3H, m), 2.15-1.81(2H, m), 1.54-1.20 (4H, m), 0.89 (3H, t, J=7.0 Hz)

Comparative Example 6

To a solution of dimethyl (3,3-difluoro-2-oxoheptyl)phosphonate (1)(0.969 g, 3.75 mmol) in anhydrous t-butyl methyl ether (15 ml), lithiumhydride (28.6 mg, 3.60 mmol) was added and the mixture was stirred fortwo hours at room temperature. (3aR,4R,5R,6aS)-2-oxo-5-phenylcarbonyloxyhexahydrocyclopenta[b]furan-4-carbaldehyde (10) (0.686 g,2.50 mmol) was added thereto and the mixed solution was stirred forapproximately 6 hours at room temperature. Water was added to thesolution and the mixture was stirred, let to stand and then separatedinto two layers. The aqueous layer was extracted twice with ethylacetate. The organic layers were combined, sequentially washed with 3%aqueous sodium chloride and saturated aqueous sodium chloride, and thendried with anhydrous magnesium sulfate. After concentration underreduced pressure, the residue was purified by silica gel columnchromatography (Fuji Silysia BW-300SP: 28 g; ethyl acetate:hexane =1:2)to give(3aR,4R,5R,6aS)-4-((E)-4,4-difluoro-3-oxo-1-octenyl)-2-oxo-5-phenylcarbonyloxyhexahydrocyclopenta[b]furan(11) (48.5 mg; 0.119 mmol; yield: 4.8%).

Example 7

To a solution of dimethyl (2-oxoheptyl)phosphonate (12) (0.178 g, 0.801mmol) in t-butyl methyl ether (2 ml), lithium hydroxide monohydrate(32.5 mg, 0.775 mmol) was added and the mixture was stirred for twohours at room temperature. A solution of methyl7-[(1R,2R,3R,5S)-5-acetoxy-2-formyl-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate(2) (0.213 g, 0.535 mmol) in t-butyl methyl ether (2 ml) and water (0.12ml) were added thereto, and the mixed solution was stirred for one hourat room temperature. The reaction mixture was added to water andextracted twice with t-butyl methyl ether. The organic layers werecombined, sequentially washed with saturated sodium bicarbonate waterand saturated aqueous sodium chloride, and then dried with anhydrousmagnesium sulfate. After concentration under reduced pressure, theresidue was purified by silica gel column chromatography (Fuji SilysiaBW-300: 100 g; ethyl acetate:hexane =3:7), to give methyl7-[(1R,2R,3R,5S)-5-acetoxy-2-((E)-3-oxo-1-octenyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate(13) (0.255 g; 0.516 mmol; yield: 96.4%) as a colorless oil.

¹H-NMR (200 MHz, CDCl₃): δ (ppm): 6.71 (0.5H, dd, J=16, 7.5 Hz), 6.68(0.5H, dd, J=16, 7.5 Hz), 6.22 (0.5H, d, J=16 Hz), 6.20 (0.5H, d, J=16Hz), 5.19-5.08 (1H, m), 4.61-4.52 (1H, m), 4.15-3.95 (1H, m), 3.90-3.60(1H, m), 3.66 (3H, s), 3.50-3.35 (1H, m), 2.75-2.35 (2H, m), 2.65 (2H,t, J=7.0 Hz), 2.29 (2H, t, J=7.5 Hz), 2.06 (3H, s), 1.90-1.15 (23H, m),0.90 (3H, t, J=7.5 Hz)

Example 8

To a solution of dimethyl (2-oxoheptyl)phosphonate (12) (0.267 g, 1.20mmol) in t-butyl methyl ether (5 ml), lithium hydroxide monohydrate(48.3 mg, 1.15 mmol) was added, and the mixture was stirred for one hourat room temperature. Water (0.05 ml) and(3aR,4R,5R,6aS)-2-oxo-5-phenylcarbonyloxyhexahydrocyclopenta[b]furan-4-carbo aldehyde (10) (0.274 g, 1.00 mmol) were addedthereto, and the mixed solution was stirred for one hour at roomtemperature. The reaction mixture was added to water and washed twicewith t-butyl methyl ether. The organic layers were combined,sequentially washed with saturated sodium bicarbonate water andsaturated aqueous sodium chloride, and then dried with anhydrousmagnesium sulfate. After concentration under reduced pressure, theresidue was purified by silica gel column chromatography (Fuji SilysiaBW-300: 100 g; ethyl acetate:hexane =2:3) to give(3aR,4R,5R,6aS)-4-((E)-3-oxo-1-octenyl)-2-oxo-5-phenylcarbonyloxyhexahydrocyclopenta[b]furan (14) (0.339 g; 0.915 mmol; yield:91.5%) as a colorless oil.

¹H-NMR (200 MHz, CDCl₃): δ (ppm): 8.05-7.95 (2H, m), 7.65-7.40 (3H, m),6.73 (1H, dd, J=16, 7.5 Hz), 6.37 (1H, dd, J=16 Hz), 5.42-5.28 (1H, m),5.19-5.06 (1H, m), 3.00-2.45 (5H, m), 2.55 (2H, J=7.0 Hz), 2.38-2.25(1H, m), 1.70-1.54 (2H, m), 1.90-1.20 (4H, m), 0.90 (3H, t, J=7.5 Hz)

(Application of the Method for the Invention)

Using the method of the invention, a therapeutically useful compound wasprepared.

To a solution of dimethyl (3,3-difluoro-2-oxoheptyl)phosphonate (1)(69.65 g, 269.8 mmol) in t-butyl methyl ether (1046 ml), lithiumhydroxide monohydrate (10.69 g, 254.8 mmol) was added and the mixturewas stirred for one hour at room temperature. A solution of methyl7-[(1R,2R,3R,5S)-5-acetoxy-2-formyl-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate(2) (59.72 g, 149.9 mmol) in t-butyl methyl ether (233 ml) and water(20.2 ml) were added thereto, and the mixed solution was heat refluxedfor approximately 41 hours (internal temperature: approximately 54° C.).After cooling to room temperature, water (351 ml) was added to thesolution and the mixture was stirred, let to stand and then separatedinto two layers. The aqueous layer was extracted twice with ethylacetate (234 ml). The organic layers were combined, washed sequentiallywith 3% aqueous sodium chloride (351 ml) and saturated aqueous sodiumchloride (351 ml), and dried with anhydrous magnesium sulfate (55 g).After concentration under reduced pressure, the residue was purified bysilica gel column chromatography (Fuji Silysia BW-300: 2280; ethylacetate:hexane =1:4). The fractions containing impurities werere-purified by silica gel column chromatography (Fuji Silysia BW-300:582 g; ethyl acetate:hexane =1:4) to give methyl7-[(1R,2R,3R,5S)-5-acetoxy-2-((E)-4,4-difluoro-3-oxo-1-octenyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate(3) (71.02 g; 133.8 mmol; yield: 89.3%) as a pale yellow oil.

To a solution of methyl7-[(1R,2R,3R,5S)-5-acetoxy-2-((E)-4,4-difluoro-3-oxo-1-octenyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate(3) (70.90 g, 133.6 mmol) in ethyl acetate (357 ml), 5%-palladium oncarbon (7.12 g) was added and the solution was hydrogenated at roomtemperature and the ambient pressure. The reaction mixture was filtered,the filtrate was concentrated under reduced pressure to give methyl7-[(1R,2R,3R,5S)-5-acetoxy-2-(4,4-difluoro-3-oxooctyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate(15) (71.02 g; 133.3 mmol; yield: 99.8%) as a colorless oil.

A solution of methyl7-[(1R,2R,3R,5S)-5-acetoxy-2-(4,4-difluoro-3-oxooctyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (15) (71.01 g, 133.3 mmol) in methanol(284 ml) was cooled to approximately −20° C., and sodium borohydride(5.08 g, 134 mmol) was added thereto. After stirring for approximately40 minutes, acetic acid (7.6 ml, 133 mmol) was added drop wise, and thereaction mixture was concentrated under reduced pressure. The residuewas supplemented with water (325 ml) and extracted three times withethyl acetate (228 mL). The organic layers were combined, washed with 3%aqueous sodium chloride (325 ml) and saturated aqueous sodium chloride(325 ml), and dried with anhydrous magnesium sulfate (51 g). Thesolution was concentrated under reduced pressure to give methyl7-[(1R,2R,3R,5S)-5-acetoxy-2-(4,4-difluoro-3-hydroxyoctyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate(16) (70.64 g; 132.1 mmol; yield: 99.1%) as a colorless oil.

A solution of methyl7-[(1R,2R,3R,5S)-5-acetoxy-2-(4,4-difluoro-3-hydroxyoctyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate(16) (70.62 g, 132.1 mmol) in ethanol (213 ml) was cooled on ice, and an8N-sodium hydroxide aqueous solution (132 ml, 1056 mmol) was addedthereto drop wise. After stirring at room temperature for approximatelyhours, the reaction mixture was concentrated under reduced pressure. Theresidue was supplemented with water (280 ml) and t-butyl methyl ether(141 ml), and cooled on ice. After 6N-hydrochloric acid was added dropwise to adjust to pH 3 to 4, the solution was extracted three times withethyl acetate (280 ml). The organic layers were combined andsequentially washed with water (280 ml) twice and saturated aqueoussodium chloride (336 ml). After drying with anhydrous magnesium sulfate(50 g), the solution was concentrated under reduced pressure to givecrude7-[(1R,2R,3R,5S)-2-(4,4-difluoro-3-hydroxyoctyl)-5-hydroxy-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanoicacid (17) as white solid. The entire amount was used in the followingstep without purification.

¹H-NMR (200 MHz, CDCl₃): δ (ppm): 4.71-4.58 (1H, m), 4.18-3.96 (2H, m),3.96-3.60 (2H, m), 3.60-3.42 (1H, m), 2.35 (2H, t, J=7.5 Hz), 2.13-1.17(30H, m), 0.93 (3H, t, J=7.1 Hz)

To the crude7-[(1R,2R,3R,5S)-2-(4,4-difluoro-3-hydroxyoctyl)-5-hydroxy-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanoicacid (17) (132.1 mmol) in acetonitrile (315 ml), diisopropyl ethylamine(69.0 ml, 369 mmol) and benzyl bromide (47.1 ml, 369 mmol) were addedand the mixture was stirred for 14 hours at room temperature. Thereaction mixture was concentrated under reduced pressure, ethyl acetate(366 ml) and water (280 ml) were added to the residue and the mixturewas stirred, let to stand and then separated into two layers. Theaqueous layer was extracted twice with ethyl acetate (224 ml). Theorganic layers were combined and washed with 1N-hydrochloric acid (336ml), saturated sodium bicarbonate water (336 ml) and saturated aqueoussodium chloride (336 ml). After drying with anhydrous magnesium sulfate(51 g), the solution was concentrated under reduced pressure. Theconcentration residue was purified by silica gel column chromatography(Fuji Silysia BW-300: 2400 g; ethyl acetate:hexane =1:2) to give benzyl7-[(1R,2R,3R,5S)-2-(4,4-difluoro-3-hydroxyoctyl)-5-hydroxy-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate(18) (74.44 g; 130.9 mmol; yield: 99.1%) as a colorless oil.

¹H-NMR (200 MHz, CDCl₃): δ (ppm): 7.42-7.26 (5H, m), 5.11 (2H, s),4.70-4.57 (1H, m), 4.18-3.96 (2H, m), 3.96-3.58 (2H, m), 3.58-3.42 (1H,m), 2.51-2.21 (2H, m), 2.35 (2H, t, J=7.4 Hz), 2.16-1.12 (29H, m), 0.93(3H, t, J=7.1 Hz)

A solution of oxalyl chloride (57.0 ml, 653 mmol) in dichloromethane(635 ml) was cooled in a dry ice-methanol bath. Dimethylsulfoxide (92.7ml, 1306 mmol) was added drop wise and the solution was stirred for 30minutes. A solution of benzyl7-[(1R,2R,3R,5S)-2-(4,4-difluoro-3-hydroxyoctyl)-5-hydroxy-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate(18) (74.31 g, 130.7 mmol) in dichloromethane (191 ml) was added dropwise, and the mixture was stirred for approximately 1.5 hours.Triethylamine (273 ml, 1959 mmol) was added drop wise to the mixture andthe reaction mixture was warmed to 0° C., saturated ammonium water (605ml) was added to the solution and the mixture was stirred, let to standand then separated into two layers. The aqueous layer was extractedtwice with dichloromethane (302 ml). The organic layers were combinedand sequentially washed with 0.35N-hydrochloric acid (302 ml), water(605 ml), saturated sodium bicarbonate water (605 ml) and saturatedaqueous sodium chloride (605 ml). After drying with anhydrous magnesiumsulfate (52 g), the solution was concentrated under reduced pressure.The residue was dissolved in a suitable amount of ethyl acetate/hexanesolvent mix (1:10), and insoluble matter was filtered. The filtrate wasconcentrated under reduced pressure and the residue was purified bysilica gel column chromatography (Fuji Silysia BW-300: 2260 g; ethylacetate:hexane =1:4) to give benzyl7-[(1R,2R,3R)-2-(4,4-difluoro-3-oxooctyl)-5-oxo-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate(19) (71.44 g; 126.5 mmol; yield: 96.8%) as a pale yellow oil.

To a solution of benzyl7-[(1R,2R,3R)-2-(4,4-difluoro-3-oxooctyl)-5-oxo-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate(19) (70.49 g, 124.8 mmol) in acetonitrile (705 ml), water (70.5 ml) and85% phosphoric acid (70.5 ml) were added and the mixture was stirred for3 hours at approximately 20° C. The solution was supplemented with 10%aqueous sodium chloride (705 ml), and extracted three times with ethylacetate (276 ml). The organic layers were combined and sequentiallywashed with 10% aqueous sodium chloride (360 ml), saturated sodiumbicarbonate water (360 ml) and saturated aqueous sodium chloride (360ml). The solution was dried with anhydrous magnesium sulfate (51 g) andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (Fuji Silysia BW-300: 2100 g; ethylacetate:hexane =1:4). The fractions containing impurities werere-purified by silica gel column chromatography (Fuji Silysia BW-3001000 g, ethyl acetate:hexane =1:4) to give benzyl7-[(2R,4aR,5R,7aR)-2-(1,1-difluoropentyl)-2-hydroxy-6-oxooctahydrocyclopenta[b]pyran-5-yl]heptanate (20) (52.64 g; 109.5 mmol; yield:87.8%) as a colorless oil.

¹H-NMR (200 MHz, CDCl₃): δ (ppm): 7.44-7.26 (5H, m), 5.11 (2H, s),4.27-4.04 (1H, m), 2.58 (1H, dd, J=17.5, 7.1 Hz), 2.35 (2H, t, J=7.4Hz), 2.24 (1H, dd, J=17.5, 11.4 Hz), 2.13-1.74 (5H, m), 1.74-1.21 (17H,m), 0.94 (3H, t, J=7.1 Hz)

To a solution of benzyl7-[(2R,4aR,5R,7aR)-2-(1,1-difluoropentyl)-2-hydroxy-6-oxooctahydrocyclopenta[b]pyran-5-yl]heptanate(20) (51.88 g, 108.0 mmol) in ethyl acetate (521 ml), 10%-palladium oncarbon (50% hydrous, 7.81 g) was added, and the solution washydrogenated at ambient pressure and at approximately 20° C. Thereaction mixture was filtered through celite, and the filtrate wasconcentrated under reduced pressure. The concentration residue waspurified by silica gel column chromatography (Fuji Silysia FL-60D: 1156g; ethyl acetate:hexane =1:2) to give a white solid (44.67 g). Thissolid was dissolved in ethyl acetate, and hexane was added drop wise torecrystallize the compound. Recrystallization was carried out twice, togive purified white crystal (36.42 g). The crystal was dissolved inethyl acetate, and filtered through a membrane filter. Hexane was addedto the filtrate to recrystallize. The crystal was recovered byfiltration and vacuum dried to give7-[(2R,4aR,5R,7aR)-2-(1,1-difluoropentyl)-2-hydroxy-6-oxooctahydrocyclopenta[b]pyran-5-yl]heptane acid (21) (35.30 g; 90.41 mmol; yield:83.7%), which is a compound that is useful as a pharmaceutical agent.

(Preparation of Starting Material)

The aldehyde (2) used in the present invention was prepared by thefollowing method.

A solution of (3aR,4S,5R,6aS)-4-(t-butyldimethylsilyloxymethyl)-5-(2-tetrahydropyranyloxy)hexahydrocyclopenta[b]furan-2-one(22) (96.7 g, 261 mmol) in toluene (600 ml) was cooled to −75° C.1.5M-diisobutyl aluminum hydride (261 ml, 392 mmol) was added theretodrop wise and the mixture was stirred at −78° C. for approximately 2hours. After adding methanol (69.0 ml, 1703 mmol) drop wise to thesolution, the solution was warmed to room temperature. Saturated aqueouspotassium sodium tartrate (800 ml) and diethyl ether (400 ml) were addedthereto and the mixture was stirred for one hour, let to stand and thenseparated into two layers. The aqueous layer was extracted twice withdiethyl ether (400 ml). The organic layers were combined, washed twicewith saturated aqueous sodium chloride (800 ml) and then dried withanhydrous magnesium sulfate. The solution was concentrated under reducedpressure to give (3aR,4S,5R,6aS)-4-(t-butyldimethylsilyloxymethyl)-5-(2-tetrahydropyranyloxy)hexahydrocyclopenta[b]furan-2-ol(23) (97.8 g, quantitatively) as a slightly yellow oil.

A suspension of (4-carboxy butyl) triphenyl phosphonium bromide (289.3g, 652.6 mmol) in tetrahydrofuran (1000 ml) was cooled on ice. To thesuspension, potassium t-butoxide (146.3 g, 1304 mmol) was added and themixture was warmed to room temperature. A solution of(3aR,4S,5R,6aS)-4-(t-butyldimethylsilyloxymethyl)-5-(2-tetrahydropyranyloxy)hexahydrocyclopenta[b]furan-2-ol(23) (97.2 g, 261 mmol) in tetrahydrofuran (500 ml) was added, and theresulting solution was stirred for approximately 1.5 hours. Ice water(800 ml) was added to the reaction and the mixture was concentratedunder reduced pressure. Then, ice-cooled 1N-hydrochloric acid (600 ml)and ethyl acetate (800 ml) were added to the residue and the mixture wasstirred, let to stand and then separated into two layers. The aqueouslayer was extracted twice with ethyl acetate (400 ml). The organiclayers were combined, and washed with saturated aqueous sodium chloride(800 ml). After drying with anhydrous magnesium sulfate, the solutionwas concentrated under reduced pressure, diethyl ether (1400 ml) wasadded to the residue and the mixture was stirred for 30 minutes. Theresulting mixture was filtered, and the deposited white solid waseliminated. The filtrate was concentrated under reduced pressure to givecrude(Z)-7-[(1R,2S,3R,5S)-2-(t-butyldimethylsilyloxymethyl)-5-hydroxy-3-(2-tetrahydropyranyloxy)cyclopentyl]-5-heptenoicacid (24) (220 g) as white solid. The entire amount was used in thefollowing step without purification.

A solution of(Z)-7-[(1R,2S,3R,5S)-2-(t-butyldimethylsilyloxymethyl)-5-hydroxy-3-(2-tetrahydropyranyloxy)cyclopentyl]-5-heptenoicacid (24) (261 mmol) in acetonitrile (1000 ml) was cooled on ice.Diazabicycloundecene (156.0 ml, 1044 mmol) was added thereto and methyliodide (65.0 ml, 1044 mmol) was added drop wise to the solution. Thereaction mixture was warmed to room temperature, and stirred for 14hours. The reaction mixture was cooled on ice, diazabicycloundecene(39.0 ml, 261 mmol) and methyl iodide (16.3 ml, 261 mmol) were added,then, the mixture was stirred at room temperature for 1.25 hours. Thereaction mixture was again cooled on ice, and diazabicycloundecene (39.0ml, 261 mmol) and methyl iodide (16.3 ml, 261 mmol) were added. Afterstirring at room temperature for one hour, the reaction mixture wasconcentrated under reduced pressure. Ethyl acetate (400 ml) and water(400 ml) were added to the residue and the mixture was stirred, let tostand and then separated into two layers. The aqueous layer wasextracted twice with ethyl acetate (400 ml), the organic layers werecombined and sequentially washed with 1N-hydrochloric acid (600 ml),saturated sodium bicarbonate water (800 ml) and saturated aqueous sodiumchloride (800 ml). After drying with anhydrous magnesium sulfate, thesolution was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (Fuji Silysia BW-300: 2000g; ethyl acetate:hexane =1:3), the fractions containing impurities werere-purified by silica gel column chromatography (Fuji Silysia BW-300:190 g; ethyl acetate:hexane =1:3) to give methyl(Z)-7-[(1R,2S,3R,5S)-2-(t-butyldimethylsilyloxymethyl)-5-hydroxy-3-(2-tetrahydropyranyloxy)cyclopentyl]-5-heptenate(25) (110.4 g, 233.5 mmol, 89.5%) as colorless oil.

To a solution of methyl(Z)-7-[(1R,2S,3R,5S)-2-(t-butyldimethylsilyloxymethyl)-5-hydroxy-3-(2-tetrahydropyranyloxy)cyclopentyl]-5-heptenate(25) (109.9 g, 233.5 mmol) in ethyl acetate (450 ml), 5%-palladium oncarbon (10.98 g) was added and the mixture was hydrogenated at ambientpressure and at room temperature. The reaction mixture was filtered andthe filtrate was concentrated under reduced pressure to give methyl7-[(1R,2S,3R,5S)-2-(t-butyldimethylsilyloxymethyl)-5-hydroxy-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate(26) (110.1 g, 232.9 mmol, 99.7%) as colorless oil.

¹H-NMR (200 MHz, CDCl₃): δ (ppm): 4.75-4.65 (1H, m), 4.26-4.06 (2H, m),3.97-3.28 (4H, m), 3.67 (3H, s), 2.52 (0.5H, d, J=10.1 Hz), 2.39 (0.5H,d, J=10.1 Hz), 2.31 (2H, t, J=7.5 Hz), 2.10-1.18 (19H, m), 0.89 (4.5H,s), 0.88 (4.5H, s), 0.04 (6H, s).

A solution of methyl7-[(1R,2S,3R,5S)-2-(t-butyldimethylsilyloxymethyl)-5-hydroxy-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate(26) (109.6 g, 231.8 mmol) in dichloromethane (500 ml) was cooled onice. Pyridine (28.1 ml, 347 mmol) and acetyl chloride (24.0 ml, 349mmol) were added drop wise to the solution, and the solution was stirredat room temperature for 1.5 hours. Water (600 ml) was added to thesolution and the mixture was stirred, let to stand, separated into twolayers, and the aqueous layer was extracted twice with dichloromethane(400 ml). The organic layers were combined and washed with1N-hydrochloric acid (600 ml), saturated sodium bicarbonate water (800ml) and saturated aqueous sodium chloride (800 ml). After drying withanhydrous magnesium sulfate, the solution was concentrated under reducedpressure to give methyl7-[(1R,2S,3R,5S)-5-acetoxy-2-(t-butyldimethylsilyloxymethyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate(27) (119.2 g, 231.5 mmol, 99.9%), as slightly yellow oil.

¹H-NMR (200 MHz, CDCl₃): δ (ppm): 5.15-5.05 (1H, m), 4.76-4.53 (1H, m),4.21-4.10 (0.5H, m), 4.10-3.95 (0.5H, m), 3.95-3.39 (4H, m), 3.67 (3H,s), 2.38-1.04 (20H, m), 2.30 (2H, t, J=7.5 Hz), 2.04 (3H, s), 0.89(4.5H, s), 0.88 (4.5H, s), 0.04 (6H, s)

A solution of methyl7-[(1R,2S,3R,5S)-5-acetoxy-2-(t-butyldimethylsilyloxymethyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate(27) (118.7 g, 230.6 mmol) in tetrahydrofuran (450 ml) was cooled onice. A solution of 1M-tetra butyl ammonium fluoride (in THF, 277 ml, 277mmol) was added drop wise thereto and the mixture was stirred at roomtemperature for 20.5 hours. The reaction mixture was concentrated underreduced pressure, and the residue was purified by silica gel columnchromatography (Fuji Silysia BW-300: 2000 g; ethyl acetate:hexane =1:1).The fractions containing impurities were re-purified by silica gelcolumn chromatography (Fuji Silysia BW-300: 520 g; ethyl acetate:hexane=1:1) to give methyl7-[(1R,2S,3R,5S)-5-acetoxy-2-hydroxymethyl-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate(28) (90.64 g, 226.3 mmol, 98.1%) as colorless oil.

A solution of oxalyl chloride (28.3 ml, 324 mmol) in dichloromethane(325 ml) was cooled in a dry ice-methanol bath. Dimethylsulfoxide (46.0ml, 648 mmol) was added drop wise and the mixture was stirred forapproximately 30 minutes. A solution of methyl7-[(1R,2S,3R,5S)-5-acetoxy-2-hydroxymethyl-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate(28) (65.00 g, 162.3 mmol) in dichloromethane (170 ml) was added theretodrop wise and the mixture was stirred for approximately 1.5 hours.Triethylamine (113 ml, 811 mmol) was added drop wise to the reaction andthe reaction mixture was warmed to 0° C. Water (426 ml) was added to thereaction mixture and the mixture was stirred, let to stand and thenseparated into two layers. The aqueous layer was extracted twice witht-butyl methyl ether (266 ml). The organic layers were combined andsequentially washed with 1N-hydrochloric acid (390 ml), water (426 ml),saturated sodium bicarbonate water (426 ml) and saturated aqueous sodiumchloride (426 ml). After drying with anhydrous magnesium sulfate (54 g),the solution was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (Fuji Silysia BW-300: 1950g; ethyl acetate:hexane =3:7) to give methyl7-[(1R,2R,3R,5S)-5-acetoxy-2-formyl-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate(2) (59.74 g, 149.9 mmol; yield: 92.4%) as yellow oil.

1. Methyl 7-[(1R, 2S, 3R, 5S)-2-(t-butyldimethylsilyloxymethyl)-5-hydroxy-3-(2-tetrahydropyranyloxy) cyclopentyl]heptanate. 2.Methyl 7-[(1R, 2S, 3R, 5S)-5-acetoxy-2-(t-butyldimethylsilyloxymethyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate.